The exposome is defined as the totality of biotic and abiotic environmental exposures experienced by an individual over a lifetime, from conception to death. Exposomics is the field that studies the comprehensive and cumulative effects of physical, chemical, biological, and (psycho)social influences that impact biological systems, by integrating data from a variety of interdisciplinary methodologies and data streams to enable discovery-based analysis of the environmental influences on health and the aging process. Humans are exposed to multiple dynamic factors throughout their lives, yet our research methods and regulatory systems have not kept pace with this complexity and continue to be overly reliant on a “one exposure at a time” mindset. Exposomics provides a dynamic and systematic approach to comprehensively capture these influential factors, which can then be integrated with and enrich genomics and other ‘omics’ analyses through a multi-level, multi-modal, and multi-scale approach. This knowledge could provide a much more accurate and holistic understanding of the aging process and disease etiology, and facilitate better evidence-based decision-making for clinicians, scientists, policymakers, and regulators. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that non-genetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted. Cities are more exposed to the consequences of age-related social and demographic change and provide a diverse and complex array of environmental influences. Therefore, urban environments serve as valuable real-world testbeds for understanding the human exposome and its impact on health, particularly for measuring the interaction of external and internal exposome factors.